B cell subsets and development

Fetus liver ： B1 B

Bone Marrow ：

HSC proB preB imB mB

spleen ： NF B FP FO B

MZ B

Antigen-independent development of B cells

three major naive peripheral B-cell populations

B cell

Immunol Rev 2004; 197:206

High-affinity IgG

INSTITUTE FOR IMMUNOBIOLOGY

B cell and B cell-mediated

humoral immune response

Part II

Department of ImmunologyFudan University

Wei Xu, Ph.D021-54237749

wx2362@hotmail.com

Overview of the humoral immune response against bacterial

B cells plasma cells

Significance of humoral immunity

eliminate extracellular bacterium and toxin

eliminate extracellular virus

B cells and humoral immune response

1. Recognition of the specific Ag2. Activation, proliferation, differentiati

on2. Germinal center: later event3. General feature of Ab response

highly repetitious molecules, bacterial flagellinbacterial cell-wall polysaccharides with repeating units.

thymus-dependent (TD) antigens

B response to TD Ag requires direct contact with Th cells,

thymus-independent (TI) antigens

TI- 1 Ag

TI-2 Ag

bacterial cell-wall components, lipopolysaccharide (LPS),

Recognition of TD Ag

Directly recognize Ag

(B cell epitope)

No MHC involvement

surfaced displayed B cell-epitopes

Ab (BCR) binds the B-cell epitope directly,

TCR binds with a self-MHC-T-cell-epitope complex

B cell activation

B cell epitope

BCR-Ig/Ig -coreceptor complex

B cell epitope

BCR

Iga/b

Signal

+

Ag-C3d

CR2

CD19

Signal

+

+++

（ CD21-CD19-CD81 ） coreceptor

B cells and humoral immune response

1. Recognition of the specific Ag2. Activation, proliferation, differentiati

on2. Germinal center: later event3. General feature of Ab response

1) activation1) activation

A. 2-signal activation model

B. the help from Th cell

2) Signal transduction

3) Proliferation and differentiation

the 2-signal rule the 2-signal rule signal 1 ： BCR － B cell epitope

signal 2 ： CD40 － CD40 L

B Th

Co-sti mol

CD40L

surviveB7

survive

B cell activation requires 2 signals

Signal 3: IL-4

Signal 1 From antigen

BCR serves 2 roles:

1. Ag-induced clustering of BCRs delivers signals that initiate the activation process.

2. BCR internalize the Ag into endosome, process and present on surface for T recognition

Receptor-mediated Ag endocytosis

T cell epitope-MHC II presentationB cell epitope

Recognition of

Signal 2

Signal 1

From antigen

From ThSignal 3From Th

Antigen crosslinks mIg(BCR), generating signal 1, which leads to increased expression of class II MHC and costimulatory B7.

Antigen–BCR complexes are internalized by receptor-mediated endocytosis and degraded to peptides, which are bound by class II MHC and presented as peptide–MHC complexes.

Th cell recognizes Ag–class II MHC and B7-CD28 co-stimulation on B-cell membrane which activates TH cell.

Th cell begins to express CD40L.

Interaction of CD40 and CD40L provides signal 2.

Th cell release large quantities of cytokines(IL-4) signal 3 to support the progression of the B cell replication and differentiation.

Signal 3

Th-secreting cytokines

Regulate B cell differentiation

B cells and humoral immune response

1. Recognition of the specific Ag

2. Activation, proliferation, differentiation

1) 2-signal activation

2) signal transduction

2. Germinal center: later event

3. General feature of Ab response

PTK Src family

immunoreceptor tyrosine-based activation motif (ITAM)

Tyrosine kinase phosphorylation cascade

a genetically determined immunodeficiency disease inability to synthesize all classes of antibody. discovered in 1952 by O. C. Bruton.

Case:a young boy who had mumps 3 times and experienced 19 different episodes of serious bacterial infections during 4 years.Do not raise Abs to any vaccines.

Bruton’s disease

globulin

globulin

globulin

1937 ， Tiselius use Electrophoresis to analyze the serum proteinsWhich comprised of 5 components ：albumin 、 1 、 2 、、 globulin

Antibody ， IgG

albumin

Serum of un-immunized personElectrophoresis

cathode

anode

Pathogenesis: failures in B-cell development.

inhibition pro–B to pre–B-cell transition

In 1990s, the gene was cloned which encodes Bruton’s tyrosine kinase (Btk).

Btk play important roles in B-cell signaling vital to the function of mature B cells

Absence of Btk results in the failure of B activation and Ab generation

B cells and humoral immune response

1. Recognition of the specific Ag

2. Activation, proliferation, differentiation

1) 2-signal activation

2) signal transduction

3) proliferation

2. Germinal center: later event

3. General feature of Ab response

Early events ：follicle （ B ） -paracortex （ T ） border,

B activation and T-B activation

Small amounts of Ab production

Late events ：At the germinal center

Presence of Ag and Th

Affinity maturation

Ig class switch (IgM IgG)

Memory B

Early and late event in Ab response to TD antigen

（ T cell ）

Affinity maturation

1 、 somatic hypermutation

2 、 affinity maturation

3 、 Ig class switch

Ag Th

late event in Ab response to TD antigen in LN

Dark zone

Light zone

（ mantle zone ）

Un-activated lymphocytes

Follicular DC (FDC)

No MHC II

Bind with Ag-Ab （ IC ） by FcR ， maintain Ag for long

Provide persistent Ag signal for B cells

In presence of Ag , by Th’s co-stimulation

Point Mutation of CDR in the Ig V region

Affinity-enhanced BCR(B cell) is selected

affinity maturation

1 、 somatic hypermutation

2 、 affinity maturation

Result of somatic hypermutation of B cell

B cells with high affinity would survive

Affinity enhancement

cytokine determined

occur in single B cell

during RNA transcription

ligation of various C gene

the V region of Ig remains, the C region changed

3 、 Ig class (isotype) switch

In response to CD40-CD40L signal and IL-4 from Th cell, the activated B cells undergo the process of heavy chain isotype (class) switching leading to production of Abs with different class of heavy chain.

Without Th With Th’ help

Th cell-secreting cytokines determines the Ig class switch

CD40L signal 、 IL-4 from ThNo Th

The V gene would recombine with a downstream C region gene and the other DNA deleted

IgM IgG

1 、 somatic hypermutation

2 、 affinity maturation

3 、 Ig class switch (Th’s help)

Ag Th

late event in Ab response to TD antigen in BM

5) Fate of the activated B cell

plasma cellplasma cell ，， PCPC

move to BM? Secret high level of Abs move to BM? Secret high level of Abs

memory B cellmemory B cell

maintain in BM? Never die? maintain in BM? Never die?

follicular B plasma cells

short-lived form a germinal centre plasma cells

1 ． plasma cell

follicle

long-lived plasma cell Bone Marrow

marginal-zone B plasma cells

Bm

Early stage

Th

later

Formation of plasma cells

Nat Rev Immunol 2005; 5:232

plasma cells

crucial survival signals (BM)

BAFF- BCMAIL-6- IL-6R

Long-lived plasma cells in the bone marrow

内皮细胞选择素血管细胞黏附分子

retention of plasma cells in BM

somatic mutationclass-switch

CXCR4

B-cell-activating factor

survival signals

BCMA ： receptor B-cellmaturation antigen

Germinal Center

B cell response to B cell response to TI antigenTI antigen

CD5 ＋ B1

Low-affinity IgM

No help from Th

No class switch (no IgG)

Signal 1 ： Ag

Signal 2 ： mitogen

Mitogen receptor

Polyclonal strong B activation

Mitogen receptor

BCR

Signal 1 ： cross-linking of lots of BCR

By polymeric saccharide

B cell response to B cell response to TI-2 antigenTI-2 antigen

Repetitive units

B cells and humoral immune response

1. Recognition of the specific Ag

2. Activation, proliferation, differentiation

2. Germinal center: later event

3. General feature of Ab response

The general feature of humoral immunity

primary response

Mostly IgM with low affinity ， IgG

secondary response

Mostly IgG with high affinity and high level

primary immune response

① lag phase: long

5 － 10 days

② log phase

③ plateu phase

short

④ decline phase

quickly

Mostly IgM, later IgG, low level and affinity

secondary immune response

① long

Lag phase: short, 1-3 days ， quickly to the top

② strong

The Ab level is 10 times more than that of the primary response

③ most IgG

enhanced affinity

mB act as APC ， with high mB7 ， and high-affinity BCR, small amounts of Ag can stimulate mB

5-10 days 1-3 days

4 、受体修正 (receptor revision)

生发中心内 识别自身抗原的 B 细胞发生 Ig V(D)J 基因的二次重排，使 BCR 被修正为针对非自身抗原。清除自身反应性 B 细胞使针对外来抗原的 BCR 具有更广泛的多样性。

Where do Th and B cell encounter ？follicle （ B ） -paracortex （ T ） boundary

（ T cell ）

Ag 特异性 T （蓝色）向滤泡边缘移动

Ag 特异性 B （蓝色）向滤泡边缘移动

Ag 特异性 T （棕色）

Ag 特异性 B （蓝色）

在滤泡边缘相遇

滤泡区： B

T

副皮质区： T

B